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Thymus Gene Coexpression Networks: A Comparative Study in Children with and Without Down Syndrome

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Transcriptomics in Health and Disease

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Abstract

In this chapter we characterized trisomy 21-driven transcriptional alterations in human thymus through gene coexpression network (GCN) analysis. We used whole thymic tissue (corticomedullar sections)—obtained at heart surgery from Down syndrome (DS) and karyotipically normal individuals (CT)—and a network-based approach for GCN analysis allowing the study of interactions between all the system’s constituents based on community detection. Changes in the degree of connections observed for hierarchically important hubs in DS and CT gene networks corresponded to sub-network changes, i.e. module (communities) changes. Distinct communities of highly interconnected gene sets were topologically identified for DS and CT networks. Trisomy 21 gene dysregulation in thymus may therefore be viewed as the breakdown and altered reorganization of functional modules.

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References

  • Abramson J, Giraud M, Benoist C et al (2010) Aire’s partners in the molecular control of immunological tolerance. Cell 140:123–135

    Article  CAS  PubMed  Google Scholar 

  • Aït Yahya-Graison E, Aubert J, Dauphinot L et al (2007) Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. Am J Hum Genet 81:475–91

    Article  PubMed Central  PubMed  Google Scholar 

  • Anderson G, Takahama Y (2012) Thymic epithelial cells: working class heroes for T cell development and repertoire selection. Trends Immunol 33:256–263

    Article  CAS  PubMed  Google Scholar 

  • Awad S, Al-Dosari MS, Al-Yacoub N et al (2013) Mutation in PHC1 implicates chromatin remodeling in primary microcephaly pathogenesis. Hum Mol Genet 22:2200–2213

    Article  CAS  PubMed  Google Scholar 

  • Banchereau R, Jordan-Villegas A, Ardura M et al (2012) Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections. PLoS ONE 7(4):e34390

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bando SY, Silva FN, Costa Lda F et al (2013) Complex network analysis of CA3 transcriptome reveals pathogenic and compensatory pathways in refractory temporal lobe epilepsy. PLoS ONE 8:e79913

    Article  PubMed Central  PubMed  Google Scholar 

  • Barabási AL, Oltvai ZN (2004) Network biology: understanding the cell’s functional organization. Nat Rev Genet 5:101–113

    Article  PubMed  Google Scholar 

  • Barabási AL, Gulbahce N, Loscalzo J (2011) Network medicine: a network based approach to human disease. Nat Rev Genet 13:56–68

    Article  Google Scholar 

  • Barnard A, Layton D, Hince M et al (2008) Impact of the neuroendocrine system on thymus and bone marrow function. Neuroimmunomodulation 15:7–18

    Article  CAS  PubMed  Google Scholar 

  • Berthelot JM, le Goff B, Maugars Y (2010) Thymic Hassall’s corpuscles, regulatory T-cells, and rheumatoid arthritis. Semin Arthritis Rheum 39:347–355

    Article  CAS  PubMed  Google Scholar 

  • Bloemers BL, Bont L, de Weger RA et al (2011) Decreased thymic output accounts for decreased naive T cell numbers in children with Down syndrome. J Immunol 186:4500–4507

    Article  CAS  PubMed  Google Scholar 

  • Blondel VD, Guillaume JL, Lambiotte R et al (2008) Fast unfolding of communities in large networks. J Stat Mech. doi:10.1088/1742-5468/2008/10/P10008

    Google Scholar 

  • Boada-Romero E, Letek M, Fleischer A et al (2013) TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3. EMBO J 32:566–582

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chaussabel D, Baldwin N (2014) Democratizing systems immunology with modular transcriptional repertoire analyses. Nat Rev Immunol 14:271–280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chen H, Xu C, Jin Q et al (2014) S100 protein family in human cancer. Am J Cancer Res 4:89–115

    PubMed Central  PubMed  Google Scholar 

  • Clauset A, Newman MEJ, Moore C (2004) Finding community structure in very large networks. Phys Rev E 70:066111

    Article  Google Scholar 

  • De Leon-Luis J, Santolaya J, Gamez F et al (2011) Sonographic thymic measurements in Down syndrome fetuses. Prenat Diagn 31:841–845

    PubMed  Google Scholar 

  • Drumea-Mirancea M, Wessels JT, Müller CA et al (2006) Characterization of a conduit system containing laminin-5 in the human thymus: a potential transport system for small molecules. J Cell Sci 119:1396–1405

    Article  CAS  PubMed  Google Scholar 

  • Estève PO, Terragni J, Deepti K et al (2014) Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (Cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation. J Biol Chem 289:8277–8287

    Article  PubMed Central  PubMed  Google Scholar 

  • Gallo EM, Winslow MM, Canté-Barrett K et al (2007) Calcineurin sets the bandwidth for discrimination of signals during thymocyte development. Nature 450:731–735

    Article  CAS  PubMed  Google Scholar 

  • Gérard A, Ghiotto M, Fos C et al (2009) Dok-4 is a novel negative regulator of T cell activation. J Immunol 182:7681–7689

    Article  PubMed Central  PubMed  Google Scholar 

  • Guillemot L, Spadaro D, Citi S (2013) The junctional proteins cingulin and paracingulin modulate the expression of tight junction protein genes through GATA-4. PLoS ONE 8:e55873

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Guittard G, Gérard A, Dupuis-Coronas S et al (2009) Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells. J Immunol 182:3974–3978

    Article  CAS  PubMed  Google Scholar 

  • Hamazaki Y, Fujita H, Kobayashi T et al (2007) Medullary thymic epithelial cells expressing Aire represent a unique lineagederived from cells expressing claudin. Nat Immunol 8:304–311

    Article  CAS  PubMed  Google Scholar 

  • Hirao K, Natsuka Y, Tamura T et al (2006) EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannosetrimming. J Biol Chem 281:9650–9658

    Article  CAS  PubMed  Google Scholar 

  • Holländer GA (2007) Claudins provide a breath of fresh Aire. Nat Immunol 8:234–236. PubMed PMID: 17304232

    Article  PubMed  Google Scholar 

  • Ishihara M, Araya N, Sato T et al (2013) Preapoptotic protease calpain-2 is frequently suppressed in adult T-cell leukemia. Blood 121:4340–4347

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Izsepi E, Himer L, Szilagyi O et al (2013) Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function. Cytometry A 83:185–196

    Article  PubMed  Google Scholar 

  • Jablonska-Mestanova V, Sisovsky V, Danisovic L et al (2013) The normal human newborns thymus. Bratisl Lek Listy 114:402–408

    CAS  PubMed  Google Scholar 

  • Kammerer R, Stober D, Singer BB et al (2001) Carcinoembryonic antigen-related cell adhesion molecule 1 on murine dendritic cells is a potent regulator of T cell stimulation. J Immunol 166:6537–6544

    Article  CAS  PubMed  Google Scholar 

  • Kanzaki S, Yamaguchi A, Yamaguchi K et al (2010) Thymic alterations in GM2 Gangliosidoses model mice. PLoS ONE 5(8):e12105

    Article  PubMed Central  PubMed  Google Scholar 

  • Karl K, Heling KS, Sarut Lopez A et al (2012) Thymic-thoracic ratio in fetuses with trisomy 21, 18 or 13. Ultrasound Obstet Gynecol 40:412–417

    Article  CAS  PubMed  Google Scholar 

  • Kim W, Bennett EJ, Huttlin EL et al (2011) Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell 44:325–340

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim S, Hill A, Warman ML et al (2012) Golgi disruption and early embryonic lethality in mice lacking USO1. PLoS ONE 7(11):e50530

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Korbel JO, Tirosh-Wagner T, Urban AE et al (2009) The genetic architecture of Down syndrome phenotypes revealed by high-resolution analysis of human segmental trisomies. Proc Natl Acad Sci U S A 106:12031–12036

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Krishnan N, Thellin O, Buckley DJ et al (2003) Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo. Endocrinology 144:2102–2110

    Article  CAS  PubMed  Google Scholar 

  • Kusters MA, Gemen EF, Verstegen RH et al (2010) Both normal memory counts and decreased naive cells favor intrinsic defect over early senescence of Down syndrome T lymphocytes. Pediatr Res 67:557–562

    Article  PubMed  Google Scholar 

  • Larocca LM, Lauriola L, Ranelletti FO et al (1990) Morphological and immunohistochemical study of Down syndrome thymus. J Med Genet Suppl. 7:225–230

    CAS  PubMed  Google Scholar 

  • Levin SM, Schlesinger Z, Handzel T et al (1979) Thymic deficiency in Down’s syndrome. Pediatrics 63:80–87

    CAS  PubMed  Google Scholar 

  • Liang H, Coles AH, Zhu Z et al (2007) Noncanonical Wnt signaling promotes apoptosis in thymocyte development. J Exp Med 204:3077–3084

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lima FA, Moreira-Filho CA, Ramos PL et al (2011) Decreased AIRE expression and global thymic hypofunction in Down syndrome. J Immunol 187:3422–3430

    Article  CAS  PubMed  Google Scholar 

  • Lorenzo LP, Shatynski KE, Clark S et al (2013) Defective thymic progenitor development and mature T-cell responses in a mouse model for Down syndrome. Immunology 139:447–458

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Low SH, Vasanji A, Nanduri J et al (2006) Syntaxins 3 and 4 are concentrated in separate clusters on the plasma membranebefore the establishment of cell polarity. Mol Biol Cell 17:977–989

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Macedo C, Evangelista AF, Magalhães DA et al (2009) Evidence for a network transcriptional control of promiscuous gene expression in medullary thymic epithelial cells. Mol Immunol 46:3240–3244

    Article  CAS  PubMed  Google Scholar 

  • Markus MA, Morris BJ (2009) RBM4: a multifunctional RNA-binding protein. Int J Biochem Cell Biol 41:740–743

    Article  CAS  PubMed  Google Scholar 

  • Mathis D, Benoist C (2009) Aire. Annu Rev Immunol 27:287–312

    Article  CAS  PubMed  Google Scholar 

  • Mégarbané A, Ravel A, Mircher C et al (2009) The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and treatment of Down syndrome. Genet Med 11:611–616

    Article  PubMed  Google Scholar 

  • Mingueneau M, Kreslavsky T, Gray D et al (2013) The transcriptional landscape of αβ T cell differentiation. Nat Immunol 14:619–632

    Article  CAS  PubMed  Google Scholar 

  • Morgan D, Goodship J, Essner JJ et al (2002) The left-right determinant inversin has highly conserved ankyrin repeat and IQ domains and interacts with calmodulin. Hum Genet 110:377–384

    Article  CAS  PubMed  Google Scholar 

  • Mou F, Praskova M, Xia F et al (2012) The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. J Exp Med 209:741–759

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nakayama F, Umeda S, Ichimiya T et al (2013) Sulfation of keratan sulfate proteoglycan reduces radiation-induced apoptosis in human Burkitt’s lymphoma cell lines. FEBS Lett 587:231–237

    Article  CAS  PubMed  Google Scholar 

  • Narayanan T, Subramaniam S (2013) Community structure analysis of gene interaction networks in Duchenne Muscular Dystrophy. PLoS ONE 8(6):e67237

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Newman MEJ, Girvan M (2004) Finding and evaluating community structure in networks. Phys Rev E 69:026113

    Article  CAS  Google Scholar 

  • Obermoser G, Presnell S, Domico K et al (2013) Systems scale interactive exploration reveals quantitative and qualitative differences in response to influenza and pneumococcal vaccines. Immunity 38:831–844

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Oh J, Wu N, Baravalle G et al (2013) MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells. J Exp Med 210:1069–1077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pellegrini FP, Marinoni M, Frangione V et al (2012) Down syndrome, autoimmunity and T regulatory cells. Clin Exp Immunol 169:238–243

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Pereira PL, Magnol L, Sahún I et al (2009) A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of Down syndrome. Hum Mol Genet 18:4756–6926

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Prandini P, Deutsch S, Lyle R et al (2007) Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance. Am J Hum Genet 81:252–263

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Puleston DJ, Simon AK (2014) Autophagy in the immune system. Immunology 141:1–8

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ruiz JC, Bruick RK (2014) F-box and leucine-rich repeat protein 5 (FBXL5): sensing intracellular iron and oxygen. J Inorg Biochem 133:73–77

    Article  CAS  PubMed  Google Scholar 

  • Sahni N, Yi S, Zhong Q et al (2013) Edgotype: a fundamental link between genotype and phenotype. Curr Opin Genet Dev 23:649–657

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sakurai C, Hashimoto H, Nakanishi H et al (2012) SNAP-23 regulates phagosome formation and maturation in macrophages. Mol Biol Cell 23:4849–4863

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sasada T, Ghendler Y, Neveu JM et al (2001) A naturally processed mitochondrial self-peptide in complex with thymic MHC molecules functions as a selecting ligand for a viral-specific T cell receptor. J Exp Med 194:883–892

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Spitz F, Gonzalez F, Duboule D (2003) A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113:405–417

    Article  CAS  PubMed  Google Scholar 

  • Stoika R, Melmed S (2002) Expression and function of pituitary tumour transforming gene for T-lymphocyte activation. Br J Haematol 119:1070–1074

    Article  CAS  PubMed  Google Scholar 

  • Takahashi K, Yoshida N, Murakami N et al (2007) Dynamic regulation of p53 subnuclearlocalization and senescence by MORC3. Mol Biol Cell 18:1701–1709

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tanimoto K, Suzuki K, Jokitalo E et al (2011) Characterization of YIPF3 and YIPF4, cis-Golgi Localizing Yip domain family proteins. Cell Struct Funct 36:171–185

    Article  CAS  PubMed  Google Scholar 

  • Tian Y, Chang JC, Fan EY et al (2013) Adaptor complexAP2/PICALM, through interaction with LC3, targets Alzheimer’s APP-CTF forterminal degradation via autophagy. Proc Natl Acad Sci U S A 110:17071–17076

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Veland IR, Montjean R, Eley L et al (2013) Inversin/Nephrocystin-2 is required for fibroblast polarity and directional cell migration. PLoS ONE 8:e60193

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Xu Y, Li W, Liu X et al (2013) Identification of dysregulated microRNAs in lymphocytes from children with Down syndrome. Gene 530:278–286

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Youm YH, Vandanmagsar B et al (2009) Obesity accelerates thymic aging. Blood 114:3803–3812

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Young DJ, Stoddart A, Nakitandwe J et al (2014) Knockdown of Hnrnpa0, a del(5q) gene, alters myeloid cell fate in murine cells through regulation of AU-rich transcripts. Haematologica 99(6):1032–1040 PubMed PMID: 24532040

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Zhou D, Medoff BD, Chen L et al (2008) The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells. Proc Natl Acad Sci U S A 105:20321–20326

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Authors and Affiliations

  1. Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 CEP, 01246-903, São Paulo, São Paulo, Brazil

    Carlos Alberto Moreira-Filho

  2. Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, São Paulo, São Paulo, Brazil

    Silvia Yumi Bando, Fernanda Bernardi Bertonha & Magda Carneiro-Sampaio

  3. Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, São Paulo, Brazil

    Filipi Nascimento Silva & Luciano da Fontoura Costa

Authors
  1. Carlos Alberto Moreira-Filho
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  2. Silvia Yumi Bando
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  3. Fernanda Bernardi Bertonha
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  4. Filipi Nascimento Silva
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  5. Luciano da Fontoura Costa
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  6. Magda Carneiro-Sampaio
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Correspondence to Carlos Alberto Moreira-Filho .

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Editors and Affiliations

  1. Department of Genetics, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

    Geraldo A. Passos

Supporting Information (Videos)

Supporting Information (Videos)

Video 7.1 and Video 7.2—Community analysis for CO networks (DS in video 7.1 and CT in 7.2). The clusters (communities) are indicated by different colors.

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Moreira-Filho, C., Bando, S., Bertonha, F., Silva, F., Costa, L., Carneiro-Sampaio, M. (2014). Thymus Gene Coexpression Networks: A Comparative Study in Children with and Without Down Syndrome. In: Passos, G. (eds) Transcriptomics in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-11985-4_7

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